Determination of pharmacokinetics and pharmacodynamics of flunixin in calves by use of pharmacokinetic/phannacodynamic modeling

Maria F. Landoni From the Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, Hawkshead Campus, Hatfield Herts, AL9 7TA, United Kingdom.

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Fiona M. Cunningham From the Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, Hawkshead Campus, Hatfield Herts, AL9 7TA, United Kingdom.

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P. Lees From the Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, Hawkshead Campus, Hatfield Herts, AL9 7TA, United Kingdom.

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SUMMARY

Pharmacokinetic and pharmacodynamic variables of flunixin were studied in calves after IV administration of the drug at a dose rate of 2.2 mg/kg of body weight. The anti-inflammatory properties of flunixin were investigated, using a model of acute inflammation; this involved surgically implanting tissue cages at subcutaneous sites and stimulating the tissue cage granulation tissue by intracavitary injection of carrageenan. The actions of flunixin on exudate concentrations of several substances related to the inflammatory process, including proteases (metalloprotease [active and total] and cysteine and serine proteases), enzymes (lactate dehydrogenase, acid phosphatase, and β-glucuronidase [β-glu]), eicosanoid (prostaglandin E2 [pge2], leukotriene B4, and serum thromboxane B2 [txb2]) concentrations, and bradykinin (BK)-induced edema, were investigated.

Flunixin had a long elimination half-life—6.87 ± 0.49 hours—and volume of distribution was 2.11 ± 0.37 L/kg, indicating extensive distribution of the drug in the body. Body clearance was 0.20 ± 0.03 L/ kg/h.

Flunixin exerted inhibitory effects on serum txb2 and exudate pge2 concentrations, β-glu activity, and BK-induced swelling. Other enzymes and inflammatory mediators were not significantly affected. Pharmacokinetic/pharmacodynamic modeling of the data revealed similar mean concentration producing 50% of the maximal effect values for inhibition of exudate pge2 and p-glu and of BK-induced swelling (0.070 ± 0.006, 0.064 ± 0.040, and 0.061 ± 0.030 μg/ml, respectively). A lower concentration producing 50% of the maximal effect value was obtained for inhibition of serum txb2 concentration (0.023 ± 0.004 μg/ml). Differences also were observed in equilibration halflife for these actions, suggesting the existence of 3 distribution compartments correlating with 3 sites of action—a central compartment and shallow and deep peripheral compartments. Pharmacokinetic/pharma- codynamic modeling proved to be a useful analytical method, providing a quantitative description of in vivo drug pharmacodynamics and indicating possible mechanisms of action.

SUMMARY

Pharmacokinetic and pharmacodynamic variables of flunixin were studied in calves after IV administration of the drug at a dose rate of 2.2 mg/kg of body weight. The anti-inflammatory properties of flunixin were investigated, using a model of acute inflammation; this involved surgically implanting tissue cages at subcutaneous sites and stimulating the tissue cage granulation tissue by intracavitary injection of carrageenan. The actions of flunixin on exudate concentrations of several substances related to the inflammatory process, including proteases (metalloprotease [active and total] and cysteine and serine proteases), enzymes (lactate dehydrogenase, acid phosphatase, and β-glucuronidase [β-glu]), eicosanoid (prostaglandin E2 [pge2], leukotriene B4, and serum thromboxane B2 [txb2]) concentrations, and bradykinin (BK)-induced edema, were investigated.

Flunixin had a long elimination half-life—6.87 ± 0.49 hours—and volume of distribution was 2.11 ± 0.37 L/kg, indicating extensive distribution of the drug in the body. Body clearance was 0.20 ± 0.03 L/ kg/h.

Flunixin exerted inhibitory effects on serum txb2 and exudate pge2 concentrations, β-glu activity, and BK-induced swelling. Other enzymes and inflammatory mediators were not significantly affected. Pharmacokinetic/pharmacodynamic modeling of the data revealed similar mean concentration producing 50% of the maximal effect values for inhibition of exudate pge2 and p-glu and of BK-induced swelling (0.070 ± 0.006, 0.064 ± 0.040, and 0.061 ± 0.030 μg/ml, respectively). A lower concentration producing 50% of the maximal effect value was obtained for inhibition of serum txb2 concentration (0.023 ± 0.004 μg/ml). Differences also were observed in equilibration halflife for these actions, suggesting the existence of 3 distribution compartments correlating with 3 sites of action—a central compartment and shallow and deep peripheral compartments. Pharmacokinetic/pharma- codynamic modeling proved to be a useful analytical method, providing a quantitative description of in vivo drug pharmacodynamics and indicating possible mechanisms of action.

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